Nu1-pyridylalkyl-n5-substituted biguanides



. Y Patented-5ept..l, 19641v "W"- The process of compounds of this invention will be 3,147,271 more clearly understood from a consideration of the fol- N1PYRIDYLALKYLN5SUBSTITUTE g. lowing examples which are given for the purposes of illus- BGUANDES tration only and are not to be considered as limiting the Seymour L. Shapiro, Hastings on Hudson, and Louis Freedman, Bronxville, N.Y., assignors to US. Vitamin 5 Scope of me Invention m 'any Way & Pharmaceutical Corporation, New York, N.Y., a cor- EXAMPLE 1 poration of Delaware N0 DlWllg- File@ NOV 30, 1950, Sel'- NO- 725551 General procedure for the preparation of the pyridylal- 6 Claims- (CL 269-296) kyl dicyandiamides: A solution of 0.5 mole of the appro- .A 10 priate picolyl or pyridylethylamine in 500 ml. of n-butanol 1 This invention is concerned with novel N substituted was mate d under c0011 ng and Sturing Wlth 4Z m1. of 12 N pyndylalkyl blguamdes of the :Structure shown: hydrochloric acid, followed by the addition of 55.0 g.

H (0.5 mole) of sodium dicyanamide. The white suspen- Rl Il; H sion was heated lunder reflux for 6 hours with stirring.

N C/ \C N/ 15 The hot solution was filtered to separate the formed t u sodium chloride and after removal of the butanol, the

R2 NH NH R3 residue of the product was recrystallized. Typical of the wherein R1 is selected from the group consisting of picolyl syntheses, retlecting this invention, are the compounds and pyridylethyl, and R2 is selected from the group conlisted in Table I.

Table 1 PICOLYL AND PYRIDYLETHYL DICYANDIAMIDES if t Ri-N-C-N-CN Analysis, percent M.P., Yield,a No R1 Ri C. percent Formula Y Carbon Hydrogen Nitrogen Caled. Found Calcd. Found Caled. Found H 142-145 b 48 CaHsN5. .I. 54. 8 54. 1 5. 2 5. 1 40. 0 40. 7 II 147-150 57 CsHoNs 54. 8 54. 6 5. 2 5. 4 40. 0 39. 8 H 78-81 b 31 CsHuNsO 1 49. 7 49. 9 5. 7 5. 7 36. 3 35. 7 CH3 150-152 39 57. l 57. l 5. 9 5. 7 37. 0 37. 1 CH3 158-160 54 57. 1 57. 2 5. 9 6. 0 37. 0 37. 1 2-pyridyletliyl H 143-146 67 57. 1 57. 2 5. 9 6. 0 37. 0 37. 3 4-pyridylethyl. H 194-195 36 57. 1 57. 2 5. 9 6. 0 37. 0 37. 3 2-pyridylethyl CH3 165-168 b 66 59. 1 58. 9 6. 5 6. 7

4-pyridylethyl CH3 202-204 h 39 CloHlaNs 59. 1 58. 8 6. 5 6. 3 I

n Recrystallizng solvent is isopropyl alcohol-hexane unless otherwise shown. b Recrystallizing solvent is acetonitrile. Isolated, and analyses shown as monohydrate.

sisting of hydrogen and methyl, and R3 is selected from EXAMPLE 2 the groip clonsiting of ilk1yl, r1alkgl, pienyl and substi- 5.0 N1 methyl N1 (4 pyridylethyl) N5 (p chlor0 tutll p eny an dparflar. y afop my 't b d phenyD-biguanide hydrochloride: A solution lof 1.9 g. e Commun S O 1S 111m 10H are S mg ases a (0.015 mole) of p-Chiomaniiine in 4.9 mi. (0.03 mole) of are obtainable as. mono' and diacd Salts with the nop' 6 N hydrochloric acid was treated Wtih 3.0 g. of N-methylmmf: mmerl aclds suchhas. hydfrochlonc hydrobmmlc (4-pyridylethyl)-dicyandiamide `and the reaction mixture mmc Summe and phl.) 9m: acfd u Q 55 heated under reux for 5 hours. When cool, the product The compmlnds of 1s mvemlpn are Convmen y p.1e` precipitated -as Va glassy solid and was separated, and

Pared by reaction of the appropriate Rsubmutei amm@ after solution in hot water on cooling gave 2.7 g. of

hydrochloride with the novel pyridylalkyl dicyandiamides product M 212 2130 desclbedln oufcopendmg aplhcatlon' The compound was further identified as its dipicrate,

In the instance where R3 is an aryl group, the com- MB 2O9 211 (Waxl pounds are prepared by reluxing in water [Shapiro, et al. 60 AMI SlS Ca1cd for C H CIN O I C 41 0. H 7 8.

Mos. si: 3725 (1959)] when the R3NH2 group is NZmy Found@ 43.1. 1.216 32N 122g alkyl or aralkyl, the amine as the hydrochloride is fused with the appropriately substituted RlRz dicyandiamide EXAMPLE 3 over a 0.5-2 hour interval as the external temperature N1 (Z-picolyl) N5 (p chlorophenyl) biguanide is gradually raised within the range of 10U-200. 65 hydrochloride; In a manner similar to that described for 3 Example 2, substituting (2-picolyl)dicyandiamide, the product was obtained (2.1 g.), M.P. 183-185.

The product was further identified as its dipicrate, M.P. 20G-202 (water).

Analysis-Calm, for CZGHZICINIZOM: C, 41.0; H, 2.8; N, 22.1. Found: C, 41.4; H, 2.6; N, 22.3.

EXAMPLE 4 N1 methyl- N1 (2 picolyl) N5 (p chlorophenyl) biguanide hydrochloride: In a manner similar lto that described for Example 2, and substituting N-methyl-(2- picolyl)dicyandiamide, there was obtained the product (2.5 g.), M.P. 223-224".

The compound was further identified as its dipicrate, M.P. 194-196 (water).

Analyss.-Calcd. for C27H23C1N12O14: C, 41.8; H, 3.0; N, 21.7. Found: C, 41.9; H, 2.8; N, 21.1.

EXAMPLE 5 Nl methyl N1 (2 pyridylethyl) N5 (p-chlorophenyl)biguanide hydrochloride: In a manner similar Eto that described for Example 2, and substituting N-methyl- (Z-pyridylethyl)-dicyandiamide, there was obtained the product (1.7 g.), MI. 204-205.

The product was further identified as its dipicrate, M.P. 211-212 (water).

AlalySSr-Calcd. for C28H25C1N12014: C, H, Found: C, 43.3; H, 3.1.

EXAMPLE 6 N1 methyl N1 (3-picolyl) N5 (pchlorophenyl) biguanide hydrochloride: In a manner similar to that described for Example 2, substituting Nrnethyl-(3-picolyl)- dicyandamide, there was obtained Ithe product (3.25 g.), M.P. 227-228".

It was further identified as its dipicrate, M.P. 207-210 (water).

AllUIySI'S.-Calcd. fOr C27H23C1N12014: C, H, N, 21.7. Found: C, 42.1; H, 3.2; N, 22.2.

EXAMPLE 7 N1 methyl N1 (4 pyridylethyl) N5 (,B-phenethyl)biguanide hydrochloride: An intimately ground mix-ture of 2.36 g. (0.015 mole) of -phenethyl amine hy- .i

drochloride and 3.0 g. (0.015 mole) of Nmethyl-(4-pyridylethyD-dicyandiamide were heated over 1 hour as the internal temperature was raised `from 130 to 157. When cool, the formed product was granulated under ether, filtered, and recrystallized from isopropyl alcohol-hexane to give 1.33 g. of product, M.P. 20S-210.

Analysis-Calci for C18H25C1N5: C, 59.9; H, 7.0. Found: C, 59.6; H, 6.4.

In a similar manner, substituting the alkyl or aralkyl amine hydrochloride as for example: methylamine, propylamine, isobutylamine, amylamine, benzylamine, p-chlorobenzylamine, 2,4-dichlorobenzylamine, 3,4-dichlorobenzylamine, furfurylamine, phenylpropylamine, on condensation with the dicyandiamides described in Table I, under the fusion procedure above, gives the appropriately R3- substituted N1pico1y1 and pyridylethyl biguanides.

The compounds of this invention show potent anti-inflammatory properties and, in addition, have a marked capacity to induce the lysis of selected strains of B. subtilis.

The capacity to induce such lysis and, in particular, the noted ability of the compounds of this application to afford such lysis at relatively low concentrations (approximately 20 parts per million) is projectable to the application of these compounds for radiation-protective use. [Weinberg et al. Experimental Cell Research 15:625 (1958).]

The compounds of this invention, being biguanides, are also important intermediates for the preparation of triazines by reaction with esters.

It is to be understood that it is intended to cover all changes and modifications of the examples herein chosen for the purposes of illustration which do not constitute de parture from the spirit and scope of the invention.

We claim:

1. The compound selected from the group consisting of the compounds of the formula ||*N\ NH R3 and their non-toxic mineral acid salts; wherein R1 is selected from the group consisting of picolyl and pyridylethyl, R2 is selected from the group consisting of hydrogen and methyl, and R3 is selected from the group consisting of lower alkyl, phenyl, halophenyl, phenyl-lower alkyl, and halophenyl-lower alkyl.

2. The compound Il Il NH NH 3. The compound I l t a r NH la 4. The compound 5. The compound 6. The compound NH IiIH 

1. THE COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE COMPOUNDS OF THE FORMULA 